Loss of Cntnap2 Causes Axonal Excitability Deficits, Developmental Delay in Cortical Myelination, and Abnormal Stereotyped Motor Behavior.

Contactin-associated protein-like 2 (Caspr2) is found at the nodes of Ranvier and has been associated with physiological properties of white matter conductivity. Genetic variation in CNTNAP2, the gene encoding Caspr2, has been linked to several neurodevelopmental conditions, yet pathophysiological effects of CNTNAP2 mutations on axonal physiology and brain myelination are unknown. Here, we have investigated mouse mutants for Cntnap2 and found profound deficiencies in the clustering of Kv1-family potassium channels in the juxtaparanodes of brain myelinated axons. These deficits are associated with a change in the waveform of axonal action potentials and increases in postsynaptic excitatory responses. We also observed that the normal process of myelination is delayed in Cntnap2 mutant mice. This later phenotype is a likely modulator of the developmental expressivity of the stereotyped motor behaviors that characterize Cntnap2 mutant mice. Altogether, our results reveal a mechanism linked to white matter conductivity through which mutation of CNTNAP2 may affect neurodevelopmental outcomes.

Causal and functional interpretation of mu- and delta-opioid receptor profiles in mesoaccumbens and nigrostriatal pathways of an oral stereotypy phenotype.

Spontaneous stereotypic behaviours are repetitive, compulsive, topographically invariant response patterns commonly observed in captive or domestic animals, which have been linked to dysfunction of basal ganglia input/output pathways. There is evidence that endogenous opioids play a key regulatory role in basal ganglia direct and indirect pathways, but their precise role, both causally and functionally, in spontaneous stereotypic behaviour is unclear. Here we examined the profile of mu- and delta-opioid receptors (density [Bmax] and affinity [Kd]) of basal ganglia structures in stereotypy (n = 10) and non-stereotypy (n = 10) animals using a competitive ligand binding approach. Mu receptor densities were significantly higher in the nucleus accumbens (p < 0.001), ventral tegmentum area (p < 0.001) and caudate nuclei (p < 0.001) of stereotypy compared to control animals. No differences were observed for delta Bmax values in any of the brain regions studied (p > 0.15). Receptor binding affinity was only found to be significantly different between control and stereotypy animals for mu receptors on the caudate region; (p < 0.001). Our findings suggest that increased inhibition (via mu-opioid receptors) of the indirect (dorsal striatopallidal) pathways are associated with spontaneous stereotypy development. Data also suggested that different types of spontaneous stereotypies (e.g. oral versus locomotor) within or a cross species may have a different neurological basis. This may have important implications for understanding the aetiology and function of these behaviours. In some instances (oral stereotypy), the behaviour may be associated with allostasis, a process that could enhance the reward value of appetitive behaviour performance (as a starting point of stereotypy development).

Subthalamic nucleus pathology contributes to repetitive behavior expression and is reversed by environmental enrichment.

Repetitive motor behaviors are common in neurodevelopmental, psychiatric and neurological disorders. Despite their prevalence in certain clinical populations, our understanding of the neurobiological cause of repetitive behavior is lacking. Likewise, not knowing the pathophysiology has precluded efforts to find effective drug treatments. Our comparisons between mouse strains that differ in their expression of repetitive behavior showed an important role of the subthalamic nucleus (STN). In mice with high rates of repetitive behavior, we found significant differences in dendritic spine density, gene expression and neuronal activation in the STN. Taken together, these data show a hypoglutamatergic state. Furthermore, by using environmental enrichment to reduce repetitive behavior, we found evidence of increased glutamatergic tone in the STN with our measures of spine density and gene expression. These results suggest the STN is a major contributor to repetitive behavior expression and highlight the potential of drugs that increase STN function to reduce repetitive behavior in clinical populations.

Absent movement-related cortical potentials in children with primary motor stereotypies.

The underlying pathophysiologic mechanism for complex motor stereotypies in children is unknown, with hypotheses ranging from an arousal to a motor control disorder. Movement-related cortical potentials (MRCPs), representing the activation of cerebral areas involved in the generation of movements, precede and accompany self-initiated voluntary movements. The goal of this study was to compare cerebral activity associated with stereotypies to that seen with voluntary movements in children with primary complex motor stereotypies. Electroencephalographic (EEG) activity synchronized with video recording was recorded in 10 children diagnosed with primary motor stereotypies and 7 controls. EEG activity related to stereotypies and self-paced arm movements were analyzed for presence or absence of early or late MRCP, a steep negativity beginning about 1 second before the onset of a voluntary movement. Early MRCPs preceded self-paced arm movements in 8 of 10 children with motor stereotypies and in 6 of 7 controls. Observed MRCPs did not differ between groups. No MRCP was identified before the appearance of a complex motor stereotypy. Unlike voluntary movements, stereotypies are not preceded by MRCPs. This indicates that premotor areas are likely not involved in the preparation of these complex movements and suggests that stereotypies are initiated by mechanisms different from voluntary movements. Further studies are required to determine the site of the motor control abnormality within cortico-striatal-thalamo-cortical pathways and to identify whether similar findings would be found in children with secondary stereotypies.

Disentangling the neuroanatomical correlates of perseveration from unilateral spatial neglect.

Perseverative behavior, manifest as re-cancelling or re-visiting targets, is distinct from spatial neglect. Perseveration is thought to reflect frontal or parietal lobe dysfunction, but the neuroanatomical correlates remain poorly defined and the interplay between neglect and perseveration is incompletely understood. We enrolled 87 consecutive patients with diffusion-weighted, perfusion-weighted imaging, and spatial neglect testing within 24 hours of right hemisphere ischemic stroke. The degrees of spatial neglect and perseveration were analyzed. Perseveration was apparent in 46% (40/87) of the patients; 28% (24/87) showed perseveration only; 18% (16/87) showed both perseveration and neglect; and 3% (3/87) showed neglect only. Perseverative behaviors occur in an inverted "U" shape: little neglect was associated with few perseverations; moderate neglect with high perseverations; and in severe neglect targets may not enter consciousness and perseverative responses decrease. Brodmann areas of dysfunction, and the caudate and putament, were assessed and volumetrically measured. In this study, the caudate and putamen were not associated with perseveration. After controlling for neglect, and volume of dysfunctional tissue, only Brodmann area 46 was associated with perseveration. Our results further support the notion that perseveration and neglect are distinct entities; while they often co-occur, acute dorsolateral prefrontal cortex ischemia is associated with perseveration specifically.

Urgencias en trastornos del movimiento que cursan con rigidez / Movement disorder emergencies accompanied by rigidity

Introducción. En el año 2002 se definieron las urgencias en trastornos del movimiento como cualquier trastorno neurológico, agudo o subagudo, en el que la presentación clínica está dominada por un trastorno del movimiento primario, y donde un fallo en el diagnóstico precoz puede resultar en una morbimortalidad importante. En este trabajo se revisarán aquellas urgencias en trastornos del movimiento que cursan con rigidez. En primer lugar las distonías agudas, siguiendo con el Síndrome Neuroléptico Maligno y por último una miscelánea de patologías. Objetivo. Revisar los avances más notorios publicados en la literatura científica en los últimos años en aquellas patologías que cursan con rigidez. Desarrollo. Se ha revisado la literatura de los últimos años y se presentan los avances más significativos en la patogenia, diagnóstico, y tratamiento, así como las principales perspectivas futuras en dichos campos (AU)

Introduction. In 2002 movement disorder emergencies were defined as any neurological disorder, either acute or subacute, in which the clinical presentation is dominated by a primary movement disorder, and where misdiagnosis in the early stages can result in important morbidity and mortality rates. This work reviews those movement disorder emergencies that are accompanied by rigidity. These are considered in the following order: first, acute dystonias, followed by neuroleptic malignant syndrome and, lastly, an assortment of other pathologies. Aims. The purpose of this study is to review the most significant advances in pathologies accompanied by rigidity that have recently been reported in the scientific literature. Development. The literature from the last few years was reviewed and we present the most significant advances in pathogenesis, diagnosis and treatment, as well as the main future perspectives in those fields (AU)

Trastornos del movimiento en el ictus / Movement disorders in stroke

Introduccion. Los trastornos del movimiento son síntomas poco frecuentes tras un ictus, pudiendo ser hipercinéticos o hipocinéticos. Objetivo. Se han revisado los principales artículos publicados de trastornos del movimiento tras el ictus, describiendo la epidemiología, etiología, fisiopatología, relación temporal entre el ictus y la aparición del movimiento anormal, características clínicas, tratamiento y pronóstico. Desarrollo. El corea y el balismo son los trastornos del movimiento más frecuentes, y que más precozmente aparecen, siendo el parkinsonismo el que se presenta con un mayor intervalo de tiempo tras el ictus. No existe una localización específica para cada trastorno del movimiento, afectándose generalmente los ganglios basales. Habitualmente son autolimitados, pero pueden requerir tratamiento sintomático. Conclusiones. Los trastornos del movimiento tras el ictus son infrecuentes, de diferentes tipos y relación temporal, con afectación habitual de los ganglios basales y buen pronóstico (AU)

Introduction. Movement disorders are infrequent symptoms following a stroke and may be hyperkinetic or hypokinetic. Aims. A review was conducted of the most important articles published on movement disorders after a stroke, which covered the following areas: epidemiology, aetiology, pathophysiology, relationship in the time elapsed between the stroke and the appearance of abnormal movements, clinical features, treatment and prognosis. Development. Chorea and ballismus are the most frequent movement disorders and the ones that appear the earliest, parkinsonism being the one that appears after the greatest interval of time following the stroke. There is no specific location for each movement disorder, although the basal ganglia are generally involved. They are usually self-limiting but may require symptomatic treatment. Conclusions. Movement disorders following a stroke are rare, of different types with different time relationships, usually with involvement of the basal ganglia and a good prognosis (AU)

The prevalence and clinical characteristics of punding in Parkinson's disease.

BACKGROUND: Punding (the display of stereotyped, repetitive behaviors) is a relatively recently discovered feature of Parkinson's disease (PD). Little is known about the prevalence and clinical characteristics of punding in PD. METHODS: In this review, four large scientific databases were comprehensively searched for literature in relation to punding prevalence and clinical correlates in the context of PD. RESULTS: Prevalence was found to vary greatly (between 0.34 to 14%), although there were large disparities in study populations, assessment methods, and criteria. We observed an association between punding, dopaminergic medications, and impulse control disorder. Other characteristics, which may be more common among punders, include a higher severity of dyskinesia, younger age of disease onset, longer disease duration, and male gender. DISCUSSION: More research in large clinical datasets is required in many areas before conclusions are drawn. The pathophysiology behind the punding phenomenon is also poorly understood at present, rendering it difficult to develop targeted therapy. The current mainstay of treatment is the reduction in the dose of dopaminergic medications, the evidence for other suggested therapies being purely empirical.

Una revisión de las clasificaciones sobre los automatismos: a propósito de la disociación automático-voluntaria / A review of classifications of automatisms: apropos of automatic-voluntary dissociation

Introducción: Este trabajo ofrece una revisión de las clasificaciones sobre los automatismos en el contexto de enfermos afásicos (fluentes y no fluentes), intentando distinguir los componentes verbales que forman parte de la disociación automático-voluntaria. Objetivo: A partir de las principales clasificaciones realizadas en lengua inglesa, se establecerá una distinción entre lenguaje automático y lenguaje no literal. Esta distinción será la base para conocer los automatismos que pertenecen a la disociación automático-voluntaria (que llamaremos lenguaje automático) y los que no pertenecen a tal disociación (que llamaremos lenguaje no literal). Pacientes: La clasificación de los automatismos se ejemplificará gracias al corpus PerLa, realizado en la Universidad de Valencia, con cinco afásicos fluentes y cinco afásicos no fluentes. Desarrollo: A partir de la clasificación discutida y a partir del corpus PerLA se ofrecerán ejemplos de lenguaje automático y de lenguaje no literal en enfermos afásicos fluentes y no fluentes. En esta taxonomía se observará que apenas existen diferencias en el habla de estos enfermos en relación con el lenguaje automático, pero sí con el lenguaje no literal. Conclusiones: La clasificación ofrecida permitirá a los logopedas obtener una base para poder discernir entre qué automatismos pertenecen al lenguaje automático y cuáles no. La distinción entre ambas clases de lenguaje (automático y no literal) por parte de enfermos fluentes y no fluentes es una consecuencia tanto del carácter implícito del lenguaje automático como del denominado "efecto de variación de tareas" (AU)

Introduction: This article provides a review of classifications of automatisms in the context of aphasic patients (fluent and non-fluent) and attempts to identify the verbal components forming part of automatic-voluntary dissociation. Objective: Based on the main classifications carried out in English, we aimed to distinguish between automatic language and non-literal language and to use this distinction as the basis for identifying the automatisms forming part of automatic-voluntary dissociation (which we call automatic language) and those not forming part of this dissociation (which we call non-literal language). Patients: Automatisms were classified using the Perception, Language and Aphasia (PerLA) corpus, constructed at the University of Valencia, with five fluent and five non-fluent aphasic patients. Development: Based on the classification discussed and the PerLA corpus, we provide examples of automatic and non-literal language in fluent and non-fluent aphasic patients. In this taxonomy, few differences were found in the speech of these patients in relation to automatic language but greater differences were identified in non-literal language. Conclusions: The classification proposed could help speech therapists to identify which automatisms belong to automatic language and which do not. The distinction between both classes of language (automatic and non-literal) by fluent and non-fluent patients is a consequence of both the implicit character of automatic language and of the effect of task variation (AU)

Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.

Mutations in the X-linked MECP2 gene, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2), cause Rett syndrome and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia and encephalopathy with early lethality. Rett syndrome is characterized by apparently normal early development followed by regression, motor abnormalities, seizures and features of autism, especially stereotyped behaviours. The mechanisms mediating these features are poorly understood. Here we show that mice lacking Mecp2 from GABA (γ-aminobutyric acid)-releasing neurons recapitulate numerous Rett syndrome and autistic features, including repetitive behaviours. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of Rett syndrome. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase 1 (Gad1) and glutamic acid decarboxylase 2 (Gad2) levels, and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.

Methamphetamine-induced stereotypy correlates negatively with patch-enhanced prodynorphin and arc mRNA expression in the rat caudate putamen: the role of mu opioid receptor activation.

Amphetamines induce stereotypy, which correlates with patch-enhanced c-Fos expression the patch compartment of caudate putamen (CPu). Methamphetamine (METH) treatment also induces patch-enhanced expression of prodynorphin (PD), arc and zif/268 in the CPu. Whether patch-enhanced activation of any of these genes correlates with METH-induced stereotypy is unknown, and the factors that contribute to this pattern of expression are poorly understood. Activation of mu opioid receptors, which are expressed by the neurons of the patch compartment, may underlie METH-induced patch-enhanced gene expression and stereotypy. The current study examined whether striatal mu opioid receptor blockade altered METH-induced stereotypy and patch-enhanced gene expression, and if there was a correlation between the two responses. Animals were intrastriatally infused with the mu antagonist CTAP (10 microg/microl), treated with METH (7.5 mg/kg, s.c.), placed in activity chambers for 3h, and then sacrificed. CTAP pretreatment attenuated METH-induced increases in PD, arc and zif/268 mRNA expression and significantly reduced METH-induced stereotypy. Patch-enhanced PD and arc mRNA expression in the dorsolateral CPu correlated negatively with METH-induced stereotypy. These data indicate that mu opioid receptor activation contributes to METH-induced gene expression in the CPu and stereotypy, and that patch-enhanced PD and arc expression may be a homeostatic response to METH treatment.

Stereotypical hand movements in 144 subjects with Rett syndrome from the population-based Australian database.

Stereotypic hand movements are a feature of Rett Syndrome but few studies have observed their nature systematically. Video data in familiar settings were obtained on subjects (n = 144) identified from an Australian population-based database. Hand stereotypies were demonstrated by most subjects (94.4%), 15 categories were observed and midline wringing was seen in approximately 60% of subjects. There was a median of two stereotypies per subject but this number decreased with age. Clapping and mouthing of hands were more prevalent in girls younger than 8 years and wringing was more prevalent in women 19 years or older. Clapping was commoner in those with p.R306C and early truncating mutations, and much rarer in those with p.R106W, p.R270X, p.R168X, and p.R255X. Stereotypies tended to be less frequent in those with more severe mutations. Otherwise, there were no clear relationships between our categories of stereotypies and mutation. Approximately a quarter each had predominantly right and left handed stereotypies and for the remaining half, no clear laterality was seen. Results were similar for all cases and when restricted to those with a pathogenic mutation. Hand stereotypies changed with increasing age but limited relationships with MECP2 mutations were identified.

Guías clínicas para la cirugía de la epilepsia y de los trastornos del movimiento / Guidelines for the surgical treatment of the movement disorders and epilepsy

Las guías clínicas para la cirugía de los trastornos del movimiento y de la epilepsia han sido diseñadas y consensuadas por el grupo de cirugía funcional de la Sociedad Española de Neurocirugía (SENEC). Las guías son recomendaciones para la realización de ambas cirugías y el formato sobre el que están basadas son los estudios prospectivos basados en evidencia científica así como en la opinión de los componentes del grupo (AU)

The guidelines for the surgical treatment of the movement disorders and epilepsy have been performed by the functional and stereotactic group of the Spanish Society of Neurosugery (SENEC). The guidelines are recomendations in terms of indication for surgery including timing and methods. The format are supported by prospective studies based in scientific evidence and the expert opinion of the group (AU)

Neuroanatomic correlates of autism and stereotypy in children with Down syndrome.

We conducted semiautomated, atlas-based analyses of regional brain volume changes on MRIs of children and adolescents with Down syndrome (DS) (N=15), DS with comorbid autism spectrum disorder (ASD) (N=15), and age-matched or sex-matched typically developing controls (N=22). Selective volumetric changes were correlated with neurobehavioral measures to determine their functional significance. DS involved selective reduction of frontal and parietal gray matter volumes, beyond the global microencephaly typically observed in this condition. DS with comorbid ASD involved relative hyperplasia of white matter in the cerebellum and brainstem compared with DS only. Cerebellar white matter volumes were positively correlated with severity of stereotypies, a distinctive feature of ASD in DS.

Clinical characteristics and medical complications of pathologic skin picking.

OBJECTIVE: This study sought to detail the phenomenology and medical consequences of pathologic skin picking (PSP). METHOD: Sixty subjects (11.7% males) with PSP (mean+/-S.D.=33.7+/-11.6 years) were assessed. Subjects seen in a pharmacological study as well as those from an ongoing outpatient longitudinal study comprised this sample. Subjects were assessed for current and lifetime psychiatric comorbidity (using the Structured Clinical Interview for DSM-IV Axis I Disorders), clinical severity (using the Clinical Global Impression - Severity scale) and psychosocial interference due to picking (using the Sheehan Disability Scale). Clinical characteristic data, including time spent picking per day, sites picked and medical complications directly resulting from skin picking behavior, as well as family history, were also obtained. RESULTS: The mean age (+/-S.D.) of onset for PSP was 12.3+/-9.6 years. The face was the most common area picked. Subjects reported picking a mean of 107.6 min each day. Scarring, ulcerations and infections were common. Few had ever sought psychiatric treatment for their behavior. Current comorbid Axis I psychiatric conditions were found in 38.3% of the sample. Trichotillomania (36.7%), compulsive nail biting (26.7%), depressive disorder (16.7%) and obsessive-compulsive disorder (15%) were the most common current comorbid conditions. CONCLUSION: PSP appears to be time consuming and frequently associated with medical complications. Research is needed to optimize patient care for individuals with this behavior.

Anatomic correlates of stereotypies in frontotemporal lobar degeneration.

Stereotypies are common in frontotemporal lobar degeneration (FTLD) however the anatomical correlates of stereotypies are unknown. We therefore set out to compare patterns of grey matter volume loss in FTLD subjects with and without stereotypies. Subjects with a diagnosis of FTLD that met international consensus criteria were prospectively recruited and separated into those with and without stereotypies. MRI and cognitive measures were obtained and voxel-based morphometry was used to assess the patterns of grey matter volume loss in those with and without stereotypies, compared to a group of age- and gender-matched controls. Demographic and clinical features were similar between subjects with and without stereotypies. FTLD subjects with stereotypies had greater volume loss in the striatum compared to those without stereotypies. Those without stereotypies showed a more widespread and typical pattern of cortical frontotemporal loss. Stereotypies in FTLD are therefore associated with a greater proportion of striatal to cortical volume loss than those without stereotypies.

Experimental change on dopaminergic neurons in striatum of Parkinson disease rats.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by selective and progressive demise of dopamine-containing neurons in the midbrain. In this study, we observe the expression of c-Jun in the striatum of rats with 6-hydroxydopamine (6-OHDA)-lesions after apomorphine (APO) intraperitoneal injection (ip) in substantia nigra compacta (SNc), and to study the mechanism of the rotations behavior. DESIGN: The 6-OHDA was unilaterally injected into rat right SNC. The APO- induced abnormal rotations were investigated on the 1st, 4th, 7th, 14th, 21st days after lesion, respectively. Meanwhile dopaminergic degeneration and c-Jun expression were observed with microscope. Nissl's body staining and immunohistochemical method (ABC) were employed to study the changes of tyrosine hydroxylase (TH) and c-Jun in DA neurons. RESULTS: We found that the number of dopaminergic neurons decreased gradually in the lesioned site and those neurons' electron-microscopic structure was severe damaged. There were over 75% of dopaminergic neurons lost, contralateral rotations over 7 turns per minute and c-Jun expressing in the ipsilateral striatum. CONCLUSION: Dopaminergic neurons deletion may be linked to upregulation of c-Jun.

Rhythmic movement disorder (head banging) in an adult during rapid eye movement sleep.

Sleep-related rhythmic movements (head banging or body rocking) are extremely common in normal infants and young children, but less than 5% of children over the age of 5 years old exhibit these stereotyped motor behaviors. They characteristically occur during drowsiness or sleep onset rather than in deep sleep or rapid eye movement (REM) sleep. We present a 27-year-old man with typical rhythmic movement disorder that had persisted into adult life and was restricted to REM sleep. This man is the oldest subject with this presentation reported to date and highlights the importance of recognizing this nocturnal movement disorder when it does occur in adults.